Gastrointestinal peptides and adipokines are critical signalling molecules involved in controlling whole-body energy homeostasis. These circulating hormones regulate a variety of biological responses such as hunger, satiety and glucose uptake. In vivo experiments have established that these hormones also regulate bone metabolism, while associations between these hormones and bone mass have been observed in human clinical studies.
Incretins are gastrointestinal hormones that help to regulate carbohydrate metabolism in response to food intake. The two main incretins are glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), both secreted by intestinal epithelial cells. Intestinal glucagon-like peptide-2 (GLP-2) is co-secreted along with GLP-1 upon nutrient ingestion.
Gastrointestinal hormones released after meal ingestion, such as GIP and GLP-2 have been shown to regulate bone turnover; GIP has a positive effect on bone, and GLP-1 and GLP-2 regulate bone homeostasis and have a positive contribution to bone mass. However, their effects are often short-lived; therefore, other pharmacological interventions such as GLP-1R agonists and DPP-4 inhibitors in conjunction with GLP-2 injection are emerging as better candidates for preventing bone resorption.
Osteoporosis can be defined as a combination of reduced bone mass and altered bone quality, resulting in decreased bone strength with an increased risk of fractures. Gastrointestinal hormones including glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 (GLP-2) have each been implicated in bone metabolism and as potential therapies for treating osteoporosis.
GLP-2 and GLP-1 are suggested for treating osteoporosis, alone or in combination with anti-osteoporosis compounds (WO 2002/024214). A dual agonist of GIP and GLP-1 is disclosed in WO2012167744. A dual agonist of the glucagon receptor and for example GIP or GLP-2 is disclosed in WO2012138941. WO2015038938 refers to a GLP-1 R and GIPR dual agonist. Room for improvement remains in the potential therapy of bone disorders associated with reduced bone density, such as osteoporosis.